The present disclosure generally relates to peptides having antiviral properties. More particularly, the invention relates to peptides exhibiting activity against influenza viruses, to pharmaceutical compositions comprising the peptides, and to methods of using the peptides to prevent and/or treat influenza viral infections.
Outbreaks of influenza A virus continue to cause widespread morbidity and mortality worldwide. In the United States alone, an estimated 5 to 20% of the population is infected by influenza A virus annually, causing approximately 200,000 hospitalizations and 36,000 deaths. The establishment of comprehensive vaccination policies has been an effective measure to limit influenza morbidity. However, the frequent genetic drifting of the virus requires yearly reformulation of the vaccine, potentially leading to a mismatch between the viral strain present in the vaccine and that circulating. Thus, antiviral therapies against influenza virus are important tools to limit both disease severity as well as transmission.
Currently, there are two classes of influenza antivirals approved for widespread distribution, including adamantine derivatives (e.g., amantadine and rimantadine), and neuraminidase inhibitors. The adamantines target the viral M2 protein, and prevent the virus from uncoating and releasing its genetic material into the cell. In contrast, the neuraminidase inhibitors (NAIs), block the enzymatic activity of the neuraminidase (NA) surface protein, and halt viral egress. Unfortunately, there are increasing reports of emerging viruses resistant to both classes of antivirals. Due to large scale resistance, the Centers for Disease Control and Prevention and others have recommended against the use of the adamantanes for treatment or prophylaxis of influenza viruses. Thus, there is an urgent need to identify and characterize new antiviral drugs for both treatment and control of influenza.
In recent years, various peptides having activity against viruses have been disclosed. For example, a 20-amino acid peptide derived from the fibroblast growth factor 4 (FGF-4) signal sequence and designated entry blocker (EB), has been shown to display significant broad-spectrum activity against influenza viruses in vitro and in vivo. The EB peptide has been described in Jones, et al., “Inhibition of Influenza Virus Infection by a Novel Antiviral Peptide That Targets Viral Attachment to Cells, Journal of Virology, (2006) Vol. 80(24), p. 11960-11967, and in U.S. patent Application Publ. No. 2005/0130884 to Brandt, et al. and in U.S. patent Application Publ. No. 2005/0203024 also to Brandt, et al. Specifically, it has been demonstrated that in vitro, EB inhibits virus replication at concentrations of 10 μM or greater. In BALB/c mice, EB prevented clinical signs of H5N1 influenza virus infection and increased survival when administered pre- or post-infection. It has also been established that EB inhibited influenza virus attachment to cells potentially through a direct binding interaction with the viral hemagglutinin (HA) protein. However, the precise mechanism of binding has not been determined.
It has now been discovered that certain derivatives of the EB peptide exhibit antiviral activity against influenza viruses. Advantageously, the antiviral peptides of the present disclosure exhibit antiviral activity that is comparable to or better than that of EB. Additionally, because the peptides are shorter in length than EB and other known antiviral peptides, the production costs of the peptides are also decreased.